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Biomedical subjects

A Jobe

Publications and source records attributed to A Jobe.

At least 73 records · Page 4Linked to original sources
PubMed1985

Accumulation of alveolar surfactant following delivery and ventilation of premature lambs.

We studied the accumulation of surfactant in the alveoli and airways from birth to 10 h of age in 60 lambs delivered prematurely at a mean gestational age of 136 days. The lambs were delivered by cesarean section and ventilated by varying peak inspiratory pressures only to normalize arterial blood gas and pH values. Alveolar surfactant accumulation was measured either by alveolar wash after timed sacrifice or by repetitive sampling of the airways using an isotope dilution technique. The fall in specific activity of phosphatidylcholine with time was measured after the intratracheal administration of either a trace dose of 3H-labeled natural surfactant and synthetic 14C-dipalmitoylphosphatidylcholine (DPPC) at birth or a treatment dose of the same mixture at 5 h of age (about 55 mg of total surfactant lipid/kg body weight). From the change in phosphatidylcholine-specific activities and the quantities and specific activities of phosphatidylcholine measured in alveolar washes, we found that the surfactant pool sizes as estimated by alveolar wash or by the isotope dilution technique were similar. The pool size of alveolar surfactant increased fourfold from birth to 20 min of age and doubled again by 10 h of age. The shape of the curve for the accumulation of alveolar surfactant versus time was independent of the final pool size achieved at 10 h of age. Sonicates of DPPC when mixed with either a trace amount or a treatment dose of natural surfactant were treated by the premature lung in a manner indistinguishable from the phosphatidylcholine associated with natural surfactant.

Animals↗
PubMed1985

Clearance of large amounts of natural surfactants and liposomes of dipalmitoylphosphatidylcholine from the lungs of rabbits.

Three-day-old rabbits were given intratracheal injections of radiolabeled natural sheep surfactant, rabbit surfactant, or liposomes of dipalmitoylphosphatidylcholine that contained greater than three times the quantity of phosphatidylcholine present in the endogenous surfactant pool. The recoveries of radiolabeled phosphatidylcholine and total phosphatidylcholine in alveolar washes, lung tissue, and total lung (alveolar washes plus lung tissue) were measured for 72 h. Approximately half of the two natural surfactants rapidly became lung tissue associated, and phosphatidylcholine derived from the rabbit surfactant was cleared from the total lung twice as rapidly as was the phosphatidylcholine from sheep surfactant (20.7% versus 10.4% of the amount present at zero time/24 h, p less than .05). The alveolar surfactant pool size did not decrease despite the clearance of the exogenously administered material. The liposomes of dipalmitoylphosphatidylcholine were cleared from the total lung at the same rate as the rabbit surfactant phosphatidylcholine; however, compared to the natural surfactants, much less of this material became lung tissue associated. The administration of the natural rabbit surfactant did not decrease the amount of radiolabeled choline, palmitic acid, or 32P that was incorporated into lung phosphatidylcholine or the amount of labeled phosphatidylcholine that was secreted to the alveoli. However, sheep surfactant increased the percent of radiolabeled phosphatidylcholine recovered by alveolar wash. These experiments document differences in clearance rates, tissue and alveolar association patterns, and subtle effects on endogenous surfactant metabolism for two surfactants and liposomes of dipalmitoylphosphatidylcholine following intratracheal administration. Uniform metabolic responses should not be anticipated following treatments with different surfactant preparations.

Animals↗
PubMed1984

Reutilization of phosphatidylcholine analogues by the pulmonary surfactant system. The lack of specificity.

Five specific 14C-labelled analogues of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, (L-alpha-DPPC) including 1-palmitoyl-sn-glycero-3-phosphocholine, (L-alpha-lysoPC) and 2,3-dipalmitoyl-sn-glycero-1-phosphocholine (the D isomer of DPPC) were individually mixed with L-alpha-[3H]DPPC and unlabelled natural surfactant isolated from 3-day-old rabbits. The mixtures were injected intratracheally into 3-day-old rabbits which were then killed at preset times up to 72 h after injection. Phosphatidylcholine was isolated from the alveolar wash and from lamellar body fraction from each rabbit and was analyzed for the ratio of 3H-to-14C counts/min. These ratios were plotted against the time the rabbits were killed to determine whether a difference existed in the rates of reutilization of the analogues relative to L-alpha-DPPC. By 60 h L-alpha-lysoPC was reutilized at 42% of the efficiency of the L-alpha-[3H]DPPC with which it was injected. That part of the L-alpha-lyso which was reutilized had been converted to [14C]phosphatidylcholine. Each of the other four analogues was reutilized by the surfactant system as efficiently as L-alpha-DPPC. These results are most consistent with a process of bulk uptake of surfactant from the alveolar space by the Type II cell with subsequent processing for resecretion which involves minimal specificity for molecular structure.

Animals↗
PubMed1984

A protein from airways of premature lambs that inhibits surfactant function.

A protein that interfered with surfactant function was isolated from the alveolar washes of prematurely delivered and ventilated lambs. This inhibitor was recovered following sequential precipitation with polyethylene glycol, Affi-Gel Blue, and diethylaminoethyl (DEAE) cellulose chromatography as a protein of approximately 110,000 mol wt. Compared to surfactant alone or surfactant and bovine serum albumin, the purified inhibitor increased the time required for surfactant to spread, increased both maximal and minimal surface tensions, increased the percent surface area that had to be compressed to reach a minimum surface tension of less than 15 dyn/cm, and delayed the surface adsorption of surfactant. The effect of inhibitor on the minimum surface tensions of surfactant solutions was inversely related to surfactant concentration. A radioimmunoassay was used to estimate that approximately 10% of the protein from plasma of premature lambs and alveolar washes after 4 h of ventilation was inhibitory. Following the simultaneous intravascular injection of labeled inhibitor and bovine serum albumin, about 4% of the radioactivity associated with both proteins was recovered in alveolar washes and 6% was associated with lung tissue after alveolar wash. This large proportionate leakage of both proteins did not occur in other tissues. The inhibitor affected multiple measurements of surfactant function in vitro and its presence may contribute to a surfactant deficiency state in the immature lung.

Animals↗
PubMed1984

Surfactant and pulmonary blood flow distributions following treatment of premature lambs with natural surfactant.

Prematurely delivered lambs were treated with radiolabeled natural surfactant by either tracheal instillation at birth and before the onset of mechanical ventilation, or after 23 +/- 1 (+/- SE) min of mechanical ventilation. Right ventricular blood flow distributions, left ventricular outputs, and left-to-right ductal shunts were measured with radiolabeled microspheres. After sacrifice, the lungs of lambs receiving surfactant at birth inflated uniformly with constant distending pressure while the lungs of lambs treated after a period of ventilation had aerated, partially aerated, and atelectatic areas. All lungs were divided into pieces which were weighed and catalogued as to location. The amount of radiolabeled surfactant and microsphere-associated radioactivity in each piece of lung was quantified. Surfactant was relatively homogenously distributed to pieces of lung from lambs that were treated with surfactant at birth; 48% of lung pieces received amounts of surfactant within +/- 25% of the mean value. Surfactant was preferentially recovered from the aerated pieces of lungs of lambs treated after a period of mechanical ventilation, and the distribution of surfactant to these lungs was very nonhomogeneous. Right ventricular blood flow distributions to the lungs were quite homogeneous in both groups of lambs. However, in 8 of 12 lambs, pulmonary blood flow was preferentially directed away from those pieces of lung that received relatively large amounts of surfactant and toward pieces of lung that received less surfactant. This acute redirection of pulmonary blood flow distribution may result from the local changes in compliances within the lung following surfactant instillation.

Animals↗
PubMed1984

Lack of correlation of severity of lung disease with the phosphatidylcholine concentration in fetal lung fluid from premature lambs at 133-136 days gestational age.

Fetal lung fluid was collected following tracheotomy at the time of delivery of 40 premature lambs at 133-136 days gestational age. The concentration of phosphatidylcholine and saturated photophatidylcholine in fetal lung fluid was compared with the severity of lung disease of the lambs as assessed after 3 to 10 h of controlled mechanical ventilation with only peak inspiratory pressures varied to control the PCO2 values. Phosphatidylcholine concentration in fetal lung fluid did not correlate with the peak inspiratory pressures needed to ventilate the lambs, total lung compliance values, or the surfactant phosphatidylcholine pool sizes measured by alveolar wash after sacrifice. The ratio of saturated to total phosphatidylcholine was constant (0.55 +/- 0.02) and independent of concentration of phosphatidylcholine in the fetal lung fluid. The fetal lung fluid contained only about 0.7% of the final surfactant phosphatidylcholine pool released by the lambs to the alveoli after birth. Within a narrow gestational age range characterized by lung disease of widely varying severity, the phosphatidylcholine concentrations in fetal lung fluid were not predictive of the severity of lung disease.

Animals↗
PubMed1983

Route of incorporation of alveolar palmitate and choline into surfactant phosphatidylcholine in rabbits.

Intratracheal injection of 3-day-old rabbits with radioactively labeled palmitic acid and choline results in an 8-10-fold increase in the efficiency of their incorporation into surfactant phosphatidylcholine when compared to the intravenous injection of these precursors. Based on labeling patterns in microsomal, lamellar body and alveolar wash fractions, the incorporation appears to be via normal surfactant synthetic pathways. Intratracheal injection of phospholipid precursors is useful for producing relatively high specific activity natural surfactant.

Animals↗
PubMed1983

The significance of reutilization of surfactant phosphatidylcholine.

To assess the magnitude of reutilization of surfactant phosphatidylcholine, 68 3-day-old rabbits were injected intratracheally with a trace dose of [3H]choline-labeled surfactant mixed with [14C]palmitate-labeled synthetic dipalmitoylphosphatidylcholine. After timed kills we measured the total phosphatidylcholine associated counts/min in whole lung and alveolar wash and the specific activities of phosphatidylcholine in the alveolar wash, lamellar bodies, and microsomes isolated from the lung of each rabbit. Using a modification of the compartment analysis of Skinner et al. (Skinner, S. M., Clark, R. E., Baker, N., and Shipley, R. A. (1959) Am. J. Physiol. 196, 238-244), we found that surfactant phosphatidylcholine was reutilized with greater than 90% efficiency. The turnover time of the alveolar wash phosphatidylcholine was estimated to be 10.1 h and 9.3 h as measured by the 3H and 14C labels, respectively. From the ratios of alveolar wash-associated natural to synthetic phosphatidylcholine specific activities and from similar ratios obtained in 30 additional rabbits using [14C]choline-labeled natural surfactant and [3H]choline-labeled dipalmitoylphosphatidylcholine, we showed that phosphatidylcholine was reutilized intact rather than as component parts. Within 6 h of injection, the synthetic dipalmitoylphosphatidylcholine functioned metabolically as that administered in the form of natural surfactant.

Animals↗
PubMed1983

Surfactant function in respiratory distress syndrome.

Airway samples from infants with respiratory distress syndrome were recovered by suction immediately after tracheal intubation for respiratory failure. The minimum surface tension of these airway samples was 27.3 +/- 3.0 dynes/cm. Surfactant with low surface tension (1.4 +/- 1.0 dynes/cm) was recovered from these samples by centrifugation; the supernatant fractions from the samples had high minimum surface tensions. The supernatant fractions contained soluble proteins that inhibited the surface tension-lowering properties of natural sheep surfactant. Similar supernatant fractions collected from infants intubated for reasons other than respiratory distress syndrome were much less inhibitory to sheep surfactant. The minimum surface tension of sequential daily airway samples from infants with respiratory distress syndrome fell progressively to 5.7 +/- 2.4 dynes/cm on the day of extubation. These results document the presence of proteins in the airways of infants with respiratory distress syndrome that inhibit the surface tension-lowering properties of surfactant.

Animals↗
PubMed1983

Cardiovascular effects of surfactant suspensions given by tracheal instillation to premature lambs.

After delivery by cesarean section at 133-136 days gestational age, 18 lambs were supported with infant ventilators. Peak inspiratory pressure was the only ventilator setting that was changed in an attempt to normalize PCO2. The lambs were retrospectively divided into two groups based on their respiratory status before treatment. Ten lambs with PCO2 values of 38 +/- 2 mmHg (mean +/- S.E.) at 5 h of age were treated with a 15-ml suspension containing 50 mg natural sheep surfactant lipid/kg body weight. After surfactant instillation, pH fell, PCO2 increased and compliance/kg decreased transiently. Surfactant treatment did not reduce the respiratory support that these lambs required. Eight lambs with PCO2 values of 68 +/- 3 mmHg at 3 +/- 0.8 h of age responded to surfactant instillation with a decrease in PCO2 and an increase in PO2 and pH. In both groups of lambs heart rates, mean aortic pressures, and mean pulmonary artery pressures changed little after surfactant instillation. Cardiac outputs and regional blood flows measured before and after surfactant treatment were unchanged. Instillation of surfactant suspensions to premature lambs did not adversely affect cardiovascular status; however, some lambs did have a transient deterioration of lung function after surfactant instillation.

Animals↗
PubMed1983

Saturated phosphatidylcholine secretion and the effect of natural surfactant on premature and term lambs ventilated for 2 days.

Lambs prematurely delivered by cesarean section and term lambs were supported on ventilators and studied over a period of 2 days. Sequential measurements of ventilatory requirements, lung compliance, and arterial pH, pO2, and pCO2 values documented the course of the lung disease. In five premature lambs the pCO2 increased to 77 +/- 5 mm Hg (mean +/- SE) by 40.5 +/- 3.1 hr of age, at which time treatment with 50 mg natural sheep surfactant lipid/kg body weight by tracheal instillation resulted in improvements in pH, pO2, and pCO2 measurements. Radiolabeled palmitic acid was injected systemically after birth to detect the appearance of endogenously synthesized and secreted saturated phosphatidylcholine in sequential airway samples. Radiolabeled saturated phosphatidylcholine specific activity increased in a relatively linear fashion for about 30 hr in lambs treated with natural surfactant, in untreated premature lambs, and in term lambs. The study demonstrates that surfactant therapy can improve the ventilatory status of premature lambs despite many hours of ventilation for pulmonary immaturity. The overall kinetics of secretion of saturated phosphatidylcholine is similar in lambs with and without pulmonary immaturity.

Animals↗
PubMed1983

Respiratory distress syndrome--new therapeutic approaches to a complex pathophysiology.

In this review I have emphasized the complicated events that occur during the course of RDS. RDS is initiated by an inadequate pool size of functional surfactant within a structurally and functionally immature lung. Obstetric and delivery room management apparently can significantly influence surfactant function and, therefore, the incidence of RDS, possibly by affecting the permeability properties of the pulmonary vascular endothelium and alveolar epithelium. The course and severity of RDS will be further influenced by neonatal care and other occurrences such as the presence or absence of a PDA. Many details of the biochemical and physiologic events that result in RDS have not been defined, so we are currently unable to quantitatively understand how all the various factors interact during the course of RDS to give the characteristic clinical course of the disease. Variations in the magnitude and timing of these interactions will likely explain the variable manifestations of respiratory failure in the tiny infant. Within the context of the pathophysiology of RDS, surfactant replacement therapy and HFV represent two new and very different approaches to treatment. Initial clinical trials of surfactant replacement therapy in infants with RDS are encouraging, and experience with animal models indicates that such an approach will work. Replacement therapy also makes sense if one considers what is known about surfactant metabolism during RDS. However, no standard, tested, and safe preparation of surfactant is available. If past experience is any guide, it may not be easy to develop an acceptable product for general use. HFV offers an opportunity to ventilate infants with relatively high mean airway pressures but without the use of high peak airway pressures. Early clinical trials suggest the technique will benefit some infants, however no ventilators for HFV are available for clinical use. In light of the low mortality from respiratory failure in RDS and a morbidity from RDS resulting mostly from the other diseases of prematurity, these new therapeutic approaches need to be thoroughly tested and understood before general clinical use.

Cardiovascular System↗
PubMed1982

Surfactant phosphatidylcholine source, fluxes, and turnover times in 3-day-old, 10-day-old, and adult rabbits.

We have measured turnover times for alveolar surfactant phosphatidylcholine in rabbits at 3 and 10 days of age and in adult rabbits. To generate accurate estimates of the turnover time of surfactant phosphatidylcholine from lamellar bodies into the alveolar space, large numbers of rabbits at each age were injected with radiolabeled choline, palmitic acid, and phosphate. Phosphatidylcholine was isolated from lamellar body and surfactant fractions from each rabbit. Curves of specific activity versus time were analyzed using the Zilversmit equations for a two compartment precursor-product model. The curves for each labeled precursor at each age were consistent with the lamellar bodies being the sole precursors of surfactant phosphatidylcholine. The same equations were used to calculate turnover times for surfactant phosphatidylcholine; these were 8-10 h in 3- and 10-day-old rabbits but only 3 h in adult rabbits. From estimates of surfactant phosphatidylcholine pool sizes and turnover times, the flux of surfactant phosphatidylcholine was estimated to be 3.4 mumol/h in adult and 0.48 mumol/h in 3-day-old rabbits; however, the flux expressed/kg of body weight is 2.4 times larger in 3-day-old than in adult rabbits. Finally, the conservation of the radiolabeled precursors in phosphatidylcholine implies reutilization of phosphatidylcholine after synthesis and secretion.

Aging↗
PubMed1982

Increased shunt through the patent ductus arteriosus after surfactant replacement therapy.

Instillation of surfactant into the trachea of preterm infants with respiratory distress syndrome is associated with a 90% incidence of patent ductus arteriosus. We studied the effects of surfactant therapy on the ductus arteriosus in 12 preterm lambs. Flow across the ductus arteriosus and systemic blood flow were calculated from radioactive microsphere injections. All developed respiratory failure (pH less than 7.1, Paco2 greater than 60) by 30 minutes after birth. Between 30 and 60 minutes after birth, six lambs were treated with tracheal instillation of 50 mg/kg surfactant lipid. By two hours after birth, treated lambs differed significantly from controls in pH (7.27 +0.02 vs 6.97 +0.08) and Paco2 (43.3 +4.1 vs 85 + 15). There were no differences in Pao2 or PGE2 concentrations or ductus arteriosus resistance, but there was a significantly larger shunt through the ductus arteriosus in treated lambs. This increased shunt resulted from the significant drop in pulmonary vascular resistance and not from a change in patency of the ductus arteriosus. Surfactant replacement may require interventions directed specifically at the patent ductus arteriosus in sick preterm infants.

Animals↗
PubMed1982

Premature lambs rescued from respiratory failure with natural surfactant: clinical and biophysical correlates.

Thirty-four Western mixed breed lambs were delivered prematurely at 120 days gestational age (term = 150 days). Four lambs were sacrificed at birth, and four lambs were sacrificed with the onset of respiratory failure (PCO2 greater than 80 torr) at about 30 min of age. The remaining lambs were treated by tracheal instillation with 50 mg of natural sheep surfactant lipid/kg body weight. These lambs were sacrificed 10 min, 40 min, 1.5 h and 3 h after surfactant treatment. Frequent blood gas and compliance measurements documented the clinical responses of the lambs. Lungs from treated lambs showed large increase relative to untreated lungs in air volumes as assessed by pressure-volume curves and by histology. However, the pressure-volume and histologic measurements did not distinguish between the posttreatment groups of lambs. Minimum surface tensions of alveolar washes fell from greater than 30 dynes/cm to 6.3 dynes/cm 10 min after treatment and again rose to 21.6 dynes/cm within 3 h. Minimum surface tensions correlated well with the PO2 values but not with the PCO2 values measured before sacrifice. The combination of dilated distal airways and atelectasis resulted from increasing surface tensions with time and mechanical ventilation and may explain the clinical deterioration without much change in the volume of gas within the airways.

Animals↗
PubMed1982

Metabolism of exogenously administered natural surfactant in the newborn lamb.

[3H]-Palmitate labeled natural lamb surfactant and free [14C]-choline were mixed with the lung fluid of 11 term lambs at cesarean section, before the first breath. After receiving the isotope, the lambs were delivered, allowed to breathe spontaneously, and were subsequently sacrificed from 5 min to 96 h of age. Alveolar washes, lung homogenates, microsomal and lamellar body fractions of lungs, and pulmonary alveolar macrophages were examined for the presence of labeled phosphatidylcholine. Analysis of the labeled natural surfactant kinetic data revealed an apparent t 1/2 of phosphatidylcholine in the whole lung of 6.0 days. This half-life can be interpreted only as a rough estimate. Appearance of considerable [3H] labeled phosphatidylcholine in the lung homogenates demonstrated uptake of phosphatidylcholine from alveoli into lung tissue. The surfactant-associated label in homogenates was localized preferentially to lamellar body fractions. Some of the administered [14C]-choline appeared in phosphatidylcholine. Almost all of this labeled phosphatidylcholine was associated with the homogenate. Extremely small % of administered [3H] and [14C] were found in pulmonary alveolar macrophages.

Animals↗